Besides one case report (Hauck et al. 2009
), this is the first study to longitudinally evaluate the relationships between serum BDNF levels and treatment response in patients suffering from PTSD. Despite a substantial decrease of PTSD and comorbid depressive symptoms over the course of an open label trial of escitalopram monotherapy, no significant changes in peripheral BDNF levels were detected throughout the 12 week treatment. Nevertheless, lower mean serum BDNF levels over the trial were a strong predictor of good PTSD response to escitalopram, even after adjusting for the age of participants and for baseline PTSD and depression severity. This suggests that low serum BDNF is a biomarker predicting a favorable response to an intervention that is presumed to potentiate neurogenesis. This finding will need to be confirmed by larger studies.
Our finding that lower mean serum BDNF levels over the trial predicted a good PTSD response to escitalopram might be explained by the effects of BDNF in the mesolimbic dopamine pathway. In contrast to the role that BDNF has in the hippocampus, high levels of BDNF in the mesolimbic dopamine pathway may be crucial to the development and maintenance of PTSD. The mesolimbic dopamine pathway is composed of dopaminergic neurons in the midbrain ventral tegmental area (VTA) and their projections to the nucleus accumbens (NAc) (Berton et al. 2006
). It has been hypothesized that dopaminergic signaling to the NAc is involved in the appraisal and response to threats from the social environment (Insel and Fernald 2004
). BDNF is a potent excitatory neurotransmitter evoking rapid postsynaptic depolarization (Lommatzsch et al. 2005
; Kafitz et al. 1999
), and BDNF activation of tropomyosin-related kinase B (TrkB) receptors may promote dopamine release in the NAc (Graham et al. 2009
). In mice, intact BDNF function in the mesolimbic dopamine pathway is necessary for the development and the maintenance of social avoidance behavior (a core symptom of PTSD in humans) induced by defeat stress paradigm. Accordingly, the inhibition of BDNF activity in the VTA-NAc pathway exerts an antidepressant-like activity in rodents and reverses the social avoidance behavior caused by defeat stress paradigm (Berton et al. 2006
; Eisch et al. 2003
). From this perspective, high BDNF activity in this pathway might be a source of treatment resistance. Thus, if peripheral BDNF provides an indicator of activity in the VTA-NAc, then higher levels could be a predictor of poor response to treatment.
Our finding that the SSRI escitalopram ameliorated PTSD symptoms without increasing serum BDNF levels is similar to some, but not all of those reported in the field of depression. Matrisciano et al. (2009)
demonstrated that sertraline, venalfaxine and escitalopram for 24 weeks had shown comparable efficacy in 21 depressed patients (10 women); however, only escitalopram did not induce an increase in serum BDNF levels (Matrisciano et al. 2009
). On the other hand, Aydemir et al. (2006)
showed that the treatment for 6 weeks with escitalopram was effective in 20 women with MDD and led to an increase in serum BDNF levels. Although the absence of studies correlating the use of escitalopram and alterations in serum BDNF levels of patients with PTSD limits us to compare our findings to those of studies on depression, these comparisons may not be valid. PTSD and depression seem to exhibit distinct neurobiological alterations (Yehuda 2002
), and gender differences have been associated with peripheral BDNF levels (Lommatzsch et al. 2005
). The fact that we enrolled only men in our study and the two above mentioned studies on depression employed both men and women or only women limits the comparability of these studies. Although most studies on MDD have shown that serum BDNF levels increase in association with the therapeutic effects of antidepressants (Sen et al. 2008
), different antidepressant drugs have variable effects on serum BDNF levels (Matrisciano et al. 2009
). In the field of PTSD, our results accord with those of the only study investigating the effects of treatment with a SSRI on serum BDNF. In a case report of Hauck et al. (2009)
treated a patient with chronic PTSD with sertraline and psychotherapy for six weeks, and, despite the reduction in PTSD symptoms, no increase in serum BDNF levels was observed.
Although no study has demonstrated that the treatment with SSRIs increases BDNF levels in patients with PTSD, evidence suggests that the chronic use of paroxetine promotes neurogenesis in the hippocampus of these patients. In an open-label study using magnetic resonance imaging (MRI), Vermetten et al. (2003)
showed an increase of 4.6% in mean hippocampal volume of 20 patients with PTSD after treatment with paroxetine for 9–12 months (Vermetten et al. 2003
). However, it is likely that there were multiple mechanisms beyond BDNF release that were involved in this observed increase in hippocampal volume. For example, high concentrations of glutamate can damage neurons in human hippocampus, and the stress-related neurodegeneration of hippocampus can be prevented by blocking the glutamate-activated NMDA receptors (Moghaddam 2002
). Studies have shown that treatment with SSRIs reduces plasma levels of glutamate in depressed patients (Küçükibrahimoglu et al. 2009
), and that treatment with paroxetine decreases central levels of glutamate in children with obsessive-compulsive disorder (Rosenberg et al. 2000
). A recent MRI study showed that the reduction in hippocampal volume seen in patients with PTSD is restricted to the dentate gyrus (DG) and CA3 subfields (Wang et al. 2010
). Studies from animal models suggest that while the DG subfield is a key site of neurogenesis (mediated by some neurotrophins, including BDNF), the CA3 is a major target of glucocorticoids, a class of steroid hormones that are elevated under conditions of stress and promote neuronal death (Wang et al. 2010
). In addition, a study in rats showed that the administration of fluoxetine or desipramine leads to an increase in hippocampal expression of fibroblast growth factor 2, a neurotrophic factor underexpressed in hippocampus of depressed patients (Bachis et al. 2008
). Finally, studies on depressed patients show that paroxetine can effectively ameliorate symptoms without increasing serum BDNF levels (Hellweg et al. 2008
) similar to our results.
Like Hauck et al. (2010)
, we found no correlation between serum BDNF levels and severity of PTSD. However, studies comparing peripheral BDNF levels in patients with PTSD and controls show less consistent results. Hauck et al. (2010)
found that patients with PTSD (and ASD) due to recent traumas (occurred in the year of assessment), had higher serum BDNF levels than matched controls, but this difference was not significant in patients with PTSD of longer duration (i.e. greater than 4 years). This contrasts with results reported by Dell’Osso et al. (2009)
who showed that PTSD patients had lower plasma BDNF levels than matched controls independent to duration of illness. However, differences in the medication status of participants, and the type of BDNF levels measured (i.e. serum vs. plasma) in these studies could explain these apparently contradictory results. In a case report, Hauck and colleagues (2009)
also found higher serum BDNF levels in a patient with chronic PTSD at baseline, compared to healthy controls. It is noteworthy that in this the patient was already taking sertraline for 15 days before the first assessment. Thus, due to the discrepancy in the results of the few studies investigating the role of BDNF in patients with PTSD, the differences in their methods and the small sample sizes preclude any definitive conclusion about this issue.
The present work is the second to investigate the efficacy of escitalopram in treating PTSD patients. In our sample, the assessments at week 12 demonstrate that both combat and non-combat PTSD subjects showed a significant decrease in PTSD and MDD symptoms, the former evaluated by self-report and clinician-report ratings. Regarding PTSD symptoms, at the end of our study, 73.3% of subjects were considered responders to escitalopram and 46.7% achieved full remission. These results are in agreement with another 12-week open-label trial where 24 veterans with PTSD were treated with 20 mg/day of escitalopram (Robert et al. 2006
). In that study, the mean CAPS score decreased from 79.42 to 61.21, with 37.5% of participants being considered responders (characterized as a reduction ≥ 20% on CAPS scores, a more permissive criteria than ours) (Robert et al. 2006
). Although we have found a greater response to escitalopram treatment in our study, it must be noted that the subjects included in Robert et al.’s work were all veterans, a group believed to be more refractory to treatment (Brady et al. 2000
;Davidson et al. 2001
), and had higher mean CAPS score at baseline (79.42 vs. 61.81).
Although our results suggest that serum BDNF levels during treatment are a potential prognostic biomarker for response to SSRI therapy in PTSD, the present work must be interpreted in the light of some limitations. First, our data are from an open-label trial with a small sample size. The second limitation is that we used flexible doses of escitalopram (5 to 20 mg/day) in our patients. Third, it is still not known if serum BDNF is a good proxy for brain BDNF concentrations in humans. However, studies in rats show that BDNF readily crosses the blood–brain barrier in both directions through a high-capacity saturable transport system (Vega et al. 2006
), and there is a strong correlation (r=0.81) between serum and cortical BDNF (Karege et al. 2002b
). Furthermore, even if we assume that peripheral BDNF is a reliable indicator of the cortical levels (Karege et al. 2002b
), the effects of BDNF seems to vary depending on the specific site of action in the brain. For instance, in mice targeted ablation of the BDNF gene within the dentate gyrus, but not within the CA1 region of the hippocampus, results in an attenuated response to antidepressants (Adachi et al. 2008
). Fourth, neurogenesis is a very complex phenomenon that is influenced by many other unmeasured factors that play an important role in mood and anxiety, through direct actions in the hippocampus and other limbic system structures (Duman and Monteggia 2006
). Fifth, this study was comprised only of male subjects in order to minimize heterogeneity. Sixth, although we have statistically controlled for depression symptoms, our small sample and the high comorbidity rates () found in our study preclude us to completely rule out the influence of major depression disorder in serum BDNF levels. On the other hand, the high comorbidity rates found in our study are similar to those reported in general population (roughly 80%) (Kessler et al. 1995
; Creamer et al. 2001
), a fact that enhances the generalizability of our results. Finally, pill count is an imperfect measure of treatment adherence.